Field of the Invention
The present invention relates to a method for treating diseases caused by cell division or that are treated by inhibiting mitosis using inhibitors of mitosis on a specific dosing schedule.
Description of the State of Art
Inhibitors of mitosis (also called mitotic inhibitors or anti-mitotics) are important therapeutics for the treatment of diseases, and they are used in treatments for cancer, as well as anti-gout and anti-fungus agents and treating restenosis. These inhibitors of mitosis therapeutics disrupt mitosis such that the cell will no longer divide. In cancer, inhibitors of mitosis can stop cancerous growth and lead to apoptosis or exit from mitosis followed by cell death.
Many inhibitors of mitosis are known. Some inhibitors of mitosis are anti-tubulin agents. Anti-tubulin agents act on tubulin, a protein that is necessary for mitosis. Anti-tubulin agents include vinca alkaloids, taxanes and epothilones. Non-tubulin targeted inhibitors of mitosis have also been investigated as cancer therapeutics. Different inhibitors of mitosis affect different portions of the cell cycle, and sometimes other functions outside of mitosis. For instance, anti-tubulin agents can affect non-mitotic cytoskeletal functions in proliferating cells and in terminally differentiated cells. Peripheral neurotoxicity has been associated with tubulin agents. Thus, different inhibitors of mitosis may have different toxicities.
Vinca alkaloids inhibit microtubule polymerization, which thereby inhibits mitosis. Vinca alkaloids include vinblastine, vincristine, vindesine and vinorelbine. Vinblastine has been used to treat certain kinds of cancer, including Hodgkin's lymphoma, non-small cell lung cancer, breast cancer and testicular cancer. Vincristine has been used to treat certain kinds of cancer, including lymphoma, breast cancer, lung cancer and acute lymphoblastic leukemia. Vinblastine and vincristine have also been used in palliative regimens for some of the major solid tumors (See Wood, Kenneth W., et al. “Past and future of the mitotic spindle as an oncology treatment.” Current Opinion in Pharmacology. Vol. 1, Issue 4 (Aug. 1, 2001): pp. 370-377). Vindesine has been used to treat certain kinds of cancer, including leukemia, lymphoma, melanoma, breast cancer and lung cancer. Vinorelbine has been used to treat certain kinds of cancer, including breast cancer and non-small cell lung cancer.
Taxanes stabilize microtubules, thereby inactivating the microtubule function of a cell and inhibiting cell division. Taxanes include paclitaxel (including Abraxane) and docetaxel. Paclitaxel is used to treat certain kinds of cancer, including lung cancer, ovarian cancer, breast cancer and advanced forms of Kaposi's sarcoma. Docetaxel is used to treat certain kinds of cancer, including breast cancer, ovarian cancer and non-small cell lung cancer. New taxanes are also in development, for example BMS275183 (See 2006 EJC Poster: Broker, L. E., et al. “The novel oral taxanes BMS275183 has a favorable activity and toxicity profile in a twice weekly schedule; Preliminary findings from an extended phase I trial.” EJC Suppl. 2006 Abstract 644, p. 194).
Additionally, colchicine is an inhibitor of mitosis that acts as an anti-tubulin agent. Colchicine inhibits mitosis by inhibiting microtubule polymerization. Colchicine is used to treat gout.
Epothilones are a class of microtubule-stabilizing chemotherapeutic agents with activity in paclitaxel-resistant cancer cell lines (See Denduluri, Neelima, et al. “Phase II trial of ixabepilone, an epothilones B analog, given daily for three days every three weeks, in metastatic breast cancer.” Invest. New Drugs. 25 (Aug. 25, 2006): pp. 63-67). Epothilones include epothilone A, epothilone B, epothilone D and the epothilone analog ixabepilone. Ixabepilone has been approved for the treatment of aggressive metastatic or locally advanced breast cancer no longer responding to currently available chemotherapies.
Dolastatin and dolastatin analogues are inhibitors of mitosis. These compounds include dolastatin 10, dolastatin 15, synthadotin (or SYN-D or ILX651; see 2004 ASCO Abstract No. 3068, Hammond, L. A., et al. “Phase (Ph) I evaluation of the dolastatin analogue synthadotin (SYN-D; ILX651): Pooled data analysis of three alternate schedules in patients (pts) with advanced solid tumors.” J. Clin. Oncology. 2004 Suppl. Abstract 3068 14s (2004)), LU103793 and cemadotin.
Aurora kinases, including Aurora A, Aurora B and Aurora C, are serine/threonine kinases that function in mitosis. Aurora kinases have been targeted as inhibitors of mitosis. Aurora A has its function in the prophase of mitosis and is required for the centrosomes to function correctly. Aurora B functions in the attachment of the mitotic spindle to the centromere. Aurora kinase inhibitors include AZD-1152, CYC-116, AS-703569 (or R-763), MLN-8054, PHA-739358, AT-9283, SNS-314, AZD-1152-HQPA, MLN-8237, KW-2449, PF-3814735, ENMD-2076 (or ENMD-981693), PHA-739385, MK-0457 (or VX-680) and MK-5108 (or VX-689). For more, see: Gautschi, Oliver, et al. “Aurora Kinases as Anticancer Drug Targets.” Clin. Cancer Res. 14(6) (Mar. 15, 2008): pp. 1639-48.
Polo-like kinases (“Plks”), including polo-like kinase 1 (“Plk1”), polo-like kinase 2 (“Plk2”), polo-like kinase 3 (“Plk3”) and polo-like kinase 4 (“Plk4”), are involved in the formation and changes in the mitotic spindle and in the activation of CDK/cyclin complexes during mitosis. Polo-like kinases have been targeted as inhibitors of mitosis. Polo-like kinase inhibitors include ON-01910Na (or ON-1910Na or Onc-01910), BI-2536 (See: Steegmaier, Martin, et al. “BI 2536, a Potent and Selective Inhibitor of Polo-like Kinase 1, Inhibits Tumor Growth In Vivo.” Current Biology, 17 (Feb. 20, 2007): pp. 316-322) and GSK-461364 (or GSK-461364A).
Kinesins are a type of motor protein. Mitotic kinesins are enzymes essential for assembly and function of the mitotic spindle. Mitotic kinesins play essential roles during all phases of mitosis. During mitosis, kinesins organize the microtubules into the bipolar structure that is the mitotic spindle Inhibition of mitotic kinesin causes malformation or dysfunction of the mitotic spindle, frequently resulting in cell cycle arrest and apoptosis (cell death).
Among the identified mitotic kinesins is kinesin spindle protein (“KSP”). During mitosis, KSP associates with microtubules of the mitotic spindle Inhibition of KSP prevents spindle pole separation during the prometaphase, giving rise to monopolar spindles causing mitotic arrest and induction of programmed cell death. Human KSP is also called HsEg5.
United States Patent Application Publication 2006/0100161 describes compounds including 2-(3-aminopropyl)-5-(3-fluorophenyl)-N-(2-methoxyethyl)-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (hereinafter “Compound 1”), 2-(3-aminopropyl)-5-(3-fluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (hereinafter “Compound 2”), 2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (hereinafter “Compound 3”), (S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (hereinafter “Compound 4”), (R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (hereinafter “Compound 5”), and 2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-hydroxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide (hereinafter “Compound 6”). Compounds 1, 2, 3, 4, 5 and 6 (collectively the “'161 KSP Inhibitors”) are KSP inhibitors.
KSP inhibitors include ispinesib (or SB-715992 or CK-0238273; See 2008 ASCO Poster: “A Phase I-II Open-Label Trial of Ispinesib on an Alternating Dosing Schedule in Chemotherapy-Naïve Patients with Locally Advanced or Metastatic Breast Cancer (MBC).” www.cytokinetics.com/pdf/ASCO2008A.pdf), the '161 KSP Inhibitors, AZD-4877, CRx-026, SB-743921 (SB-921), MK-0731, EMD-534085 and ARQ 621. Ispinesib has been tested in a wide range of tumor types and is being tested in human clinical trials.
Among the other motor proteins that act during mitosis, small molecule inhibitors have also been described for centromere associated protein E (“CENP-E”). CENP-E is a motor protein (See Chan, G. K. T., et al. “Characterization of the Kinetochore Binding Domain of CENP-E Reveals Interactions with the Kinetochore Proteins CENP-F and hBUBR1.” J. Cell Biology. Vol. 143, No. 1 (Oct. 5, 1998): pp. 49-63) and can be classified as a type of mitotic kinesin. CENP-E inhibitors include GSK-295 (or GSK-923295).
Many inhibitors of mitosis have been tested as therapeutics for the treatment of diseases. Many non-tubulin inhibitors of mitosis have been tested clinically as therapeutics. Various dosing schedules have been used in these tests of inhibitors of mitosis. There remains a need for effective dosing schedules for inhibitors of mitosis that allows potent biological activity with manageable toxicity. There remains a particular need for effective dosing schedules for inhibitors of mitosis that allows potent anti-cancer activity with manageable toxicity.